Project Summary Certain life-saving interventions such as cardiopulmonary bypass (CPB), extracorporeal membrane oxygenation (ECMO), hemodialysis, or ventricular assist device (VAD) pumps require the use of heparin to maintain blood flow through the devices and/or to prevent downstream thromboembolic complications. Several other invasive vascular procedures also utilize temporal anticoagulation, such as during and after prosthetic vascular graft implantation. Unfortunately, antithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can have severe dose-limiting hemorrhagic toxicity. Consequently, the level of anticoagulation must be limited to balance the risk of bleeding with that of thrombosis. As a result, device failure and thrombotic complications can be frequent and devastating. Our recent studies suggest that coagulation factor XII (FXII) contributes to the progression of thrombosis, and thereby is a potential target for a new class of antithrombotic drugs. Since data also suggests that FXII does not contribute to hemostasis, and FXII deficiency is an asymptomatic condition in mammals, FXII inhibition is unlikely to have significant adverse effects. In this Phase IIB Small Market project, we will continue to develop our innovative anticoagulant drug candidate for use during ECMO and other thrombotic indications with a high bleeding risk. We are currently on track to reach all of our Phase I/II Fast-Track milestones by the beginning of Phase IIB and have: 1) confirmed that targeting FXII in our ECMO model is antithrombotic and improves the effectiveness of heparin without a detectable increase in hemostasis impairment, 2) humanized our lead murine anti-FXII antibody, which is now designated as AB054, and 3) completed development of a stable manufacturing cell line that is being used to produce a toxicology lot of AB054. We have also developed IND-enabling GLP toxicity protocols for studies that will commence at Charles River Labs (Reno, NV) upon release of our toxicology lot at the start of Phase IIB. This Small Market project, combined with our secured matching funds, will provide essential support for continued product development towards an IND application and clinical trials for the ECMO indication. Our specific aims are to: 1) determine the toxicity of the humanized anti-FXII antibody, AB054, 2) manufacture a cGMP lot of AB054 for human studies, and 3) initiate a phase 1 clinical trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of AB054. Success of this project will propel AB054 towards a phase 2 human proof-of-concept clinical trial in our proposed initial small market entry indication: safe anticoagulation during ECMO, where heparin can cause bleeding and often fails to sustain device perfusion.